Receptor tyrosine kinases (RTKs) are key regulators of critical cellular processes such as cell growth, differentiation, neo-vascularization, and tissue repair. In addition to their importance in normal physiology, aberrant expression of certain RTKs has been implicated in the development and progression of many types of cancer. These RTKs have emerged as promising drug targets for cancer therapy.
The RTK c-Met is the cell surface receptor for Hepatocyte Growth Factor (HGF), also known as scatter factor (Cooper et al. Nature 1984; 311:29-33; Bottaro et al. Science 1991; 251:802-4). HGF is a 90 kD multidomain glycoprotein that is highly related to members of the plasminogen serine protease family. Hepatocycte Growth Factor is secreted as a single-chain, inactive polypeptide by mesenchymal cells, and is cleaved by serine proteases into a 69-kDa alpha-chain and 34-kDa beta-chain. (Birchmeier et al., Nat Rev Mol Cell Biol 2003; 4:915-25). The α chain NH2-terminal portion contains the high-affinity c-Met receptor-binding domain, but the β chain is required to interact with the c-Met receptor for receptor activation (Matsumoto & Nakamura Cancer 3d 2003; 94:321-7). HGF is the only known ligand for the c-Met receptor (Birchmeier et al. Nat Rev Mol Cell Biol 2003; 4:915-25). The c-Met receptor, like its ligand, is a disulfide-linked heterodimer consisting of extracellular α and β chains. The α chain, heterodimerized to the amino-terminal portion of the β chain, forms the major ligand-binding site in the extracellular domain. The carboxy-terminal tail of c-Met includes tyrosines Y1349 and Y1356, which, when phosphorylated, serve as docking sites for intracellular adaptor proteins, leading to downstream signaling (Ponzetto et al. Mol Cell Biol 1993; 13:4600-8). The c-Met/HGF pathway is the main driver of the invasive growth program, a series of events including cell proliferation, scattering, migration, survival, and invasion of tissues. Under normal circumstances, the invasive growth program is essential for correct organ formation during embryogenesis and in adult homeostasis. Importantly, it is also involved in tumorigenesis, tumor angiogenesis and metastasis. The c-Met receptor is expressed in the epithelial cells of many organs during embryogenesis and also in adulthood, like liver, prostate, pancreas, muscle, kidney and bone marrow. In tumor cells, c-Met activation triggers diverse series of signaling cascades resulting in cell growth, proliferation, invasion, metastasis formation and escape from apoptosis. Overexpression of HGF and c-Met is indicative of increased aggressiveness of tumors and poor prognostic outcome of cancer patients. HGF and c-Met expression have been observed in most solid tumors, including; head and neck, bladder, breast, cervical, colorectal, gastric, liver, lung, ovarian, pancreatic, prostate, renal and thyroid cancers.